There are approximately 100 million people in the world and 800,000 people in the United States alone with Parkinson's disease (PD).
Parkinson's disease is a result of chronic progressive degeneration of neurons, the cause of which has not yet completely been clarified. While the primary cause of Parkinson disease is not known, it is characterized by degeneration of dopaminergic neurons of the substantia nigra (SN). The substantia nigra is a portion of the lower brain, or brain stem that helps control voluntary movements. The shortage of dopamine in the brain caused by the loss of these neurons is believed to cause the observable disease symptoms. Clinically, it manifests in the form of the cardinal symptoms resting tremors, rigor, bradykinesia, and postural instability.
Levodopa, dopamine agonists such as rotigotine, pramipexol, bromocriptine, ropinirol, cabergoline, pergolide, apomorphine and lisuride, anticholinergics, NMDA antagonists, β-blocker as well as the MAO-B inhibitor selegiline and the COMT inhibitor entacapone are used as medicines for relief from the motor symptoms. Most of these agents intervene in the dopamine and/or choline signal cascade and thereby symptomatically influence the Parkinson-typical movement disorders.
In the present therapy for the Parkinson's disease, treatment is initiated after the appearance of the cardinal symptoms. In general, Parkinson's disease is said to be clinically evident if at least two of the four cardinal symptoms (bradykinesia, resting tremors, rigor, and postural instability) are detected and respond to L-dopa (Hughes, J Neurol Neurosurg Psychiatry 55, 1992, 181). Unfortunately, the motor function disorders in Parkinson patients become apparent only after about 70-80% of the dopaminergic neurons in the substantia nigra (SN) are irreparably damaged (Becker et al, J Neurol 249, 2002, Suppl 3:III, 40; Hornykiewicz, Encyclopaedia of Life Science 2001, 1). Chances of a therapy with lasting effects are very bleak at that point. Hence, it is desirable to initiate the therapy as early as possible.
Current clinical observations as well as anatomical and genetic research show that diagnosis of Parkinson patients at an early stage and identification of high risk patients is possible. With that an opportunity arises for influencing the disease process at a point of time when more neurons are still there, rather than at the time of appearance of several cardinal motor symptoms of the Parkinson's disease, and thereby for protecting a quantitatively greater number of neurons. One can expect that the administration of an effective neuroprotective agent at an early stage will significantly delay the process of the development of the disease: The sooner the therapy is initiated, the higher are the chances of a long lasting prevention of the onset of symptoms, which degrade the quality of life.
Hence, such remedies are needed that not only influence the dopaminergic transmission and alleviate the symptoms of the Parkinson's disease in advanced stages, but also reverse, prevent, or at least significantly delay the dopaminergic neuron extinction in the early, to a great extent motor-asymptomatic, Parkinson stages (Dawson, Nature Neuroscience Supplement 5, 2002, 1058).
(+)-3-Hydroxymorphinan ((+)-3-HM) and its derivatives have shown the neuroprotective property in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models for Parkinson's disease. In this animal model, daily injections with (+)-3-HM or its analogs showed that dopamine (DA) neurons in substantia nigra pars compacta have been protected and DA levels in striatum has been restored (US Patent Publication No. 2005-0256147 A1; International Patent Publication No. WO2005/110412; Zhang et al, FASEB J. 2006 Dec. 20(14):2496-2511; Zhang et al, FASEB J. 2005 Mar. 19(3):395-397; and Kim et al. Life Science 72 (2003) 1883-1895). However, (+)-3-HM and its derivatives are efficacious only if they are administered intraperitoneally or intravenously.
The present invention relates to provide novel prodrugs of (+)-3-hydroxymorphinan which are effective as a neuroprotective agent for Parkinson's disease, when they are delivered orally.